Editors' ChoiceKidney Disease

Defining chronic kidney disease at the genetic level

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Science Translational Medicine  09 Jan 2019:
Vol. 11, Issue 474, eaaw0532
DOI: 10.1126/scitranslmed.aaw0532


Exome sequencing reveals the genetic complexity of chronic kidney disease.

In recent years, exome sequencing has been incorporated into the diagnostic approach for severe congenital abnormalities, primary immunodeficiencies, and pediatric rheumatological diseases. However, the applicability of exome sequencing to more common conditions such as chronic kidney disease (CKD) is not well explored. CKD affects nearly one in ten individuals, and few effective therapies are clinically available. In many cases, the underlying cause is unknown, although greater than 25% of patients report a family history of kidney disease. Although previous studies have established the use of genetic testing for early onset and familial cases, the utility of genetic testing in adults sporadic kidney disease is unknown. Groopman et al. established the diagnostic potential of exome sequencing for genetic diagnosis in CKD and uncovered unexpected genetic heterogeneity among individuals with this disease.

The authors carried out exome sequencing in 3037 CKD patients and discovered mutations in genes there were either previously associated with kidney disease or genes known to be important for kidney development and function in 307 (9.3%) individuals. Diagnostic utility was highest in patients with idiopathic disease (17.1%). Among the identified disease variants, 63% occurred in genes previously associated with the familial nephropathies polycystic kidney disease (PKD1, PKD2), glomerulopathy (COL4A3, COL4A4, COL4A5), and UMOD-associated tubulointerstitial disease. Intriguingly, only 38% of patients with COL4A mutations had typical manifestations (Alport syndrome or thin basement membrane disease), revealing both the sensitivity of genetic testing and the extent of phenotypic heterogeneity. The remaining mutations were found within 114 individuals across 60 distinct genes with diverse functions spanning solute transporters to transcriptional regulators.

This study provides important insights regarding the potential use of exome sequencing in prevalent diseases, including diagnostic utility, frequency of mutations associated with familial syndromes, and genetic heterogeneity. The extent of genetic heterogeneity uncovered in this cohort of chronic kidney disease patients is particularly informative as it indicates both the complexity of this condition and how much we have yet to learn regarding the pathogenesis of kidney disease. Most importantly, the authors’ observations highlight opportunities to redefine chronic kidney disease based on genetic etiology and to develop therapies that precisely target the mechanisms responsible for disease pathogenesis.

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